Reducing protein deposition events is essential for slowing the progression of Alzheimer's disease (AD), especially A[unreadable]1-42 peptide oligomers that accumulate inside and outside neurons and cause functional compromise. Finding a strategy to reduce A[unreadable] oligomeric assemblies is widely thought to be the key objective for treating AD. Accumulation of A[unreadable] peptides is one of the earliest episodes in AD, and of the several avenues being pursued for A[unreadable] clearance, a lysosomal avenue has been described that can be enhanced through small molecule modulators. Appropriate concentrations of Z-Phe-Ala- diazomethylketone (PADK) and novel derivatives have been found to cause a compensatory feedback response, resulting in 2- to 9-fold increases in lysosomal cathepsins and other hydrolytic enzymes involved in protein clearance processes. This induced enhancement of lysosomal capacity indeed promotes clearance of AD-related proteins, restores synaptic markers, and improves brain functionality in model systems including transgenic mice that express human amyloid precursor protein (hAPP) containing mutations linked to AD. The objective of the proposed Phase I experiments is to expand our library of compounds with lysosomal modulatory activity that have commercial value for reducing A[unreadable] oligomers and treating AD. The project will include the synthesis of novel modulators that possess a stable, non-peptide backbone and optimized side chains designed through structure-activity relationships. We will screen for those compounds that selectively increase the expression of lysosomal enzymes, and that enhance the clearance of A[unreadable] oligomeric species. Selected modulators will also be assessed for solubility, the ability to cross the blood brain barrier, and for stability. Lysosomal modulation represents a unique pharmacological strategy against AD and provides a foundation for a viable business entity. Lysosomal modulators will be first-in-class drugs for treating the neurodegenerative disorder either alone or in combination with current treatments in order to slow, halt or reverse the progressive cognitive decline in AD and related dementias. PUBLIC HEALTH RELEVANCE: Reducing protein accumulation is essential for slowing the progression of Alzheimer's disease (AD), especially A[unreadable] peptide oligomers that accumulate in neurons and cause functional compromise. Of the five drugs currently available for treating AD, none of them influence the hallmark pathological features of the disease. This proposal focuses on lysosomal modulatory drugs that have been shown to enhance the clearance of A[unreadable] species and other hallmark accumulation events of AD. The proposed research will develop potent lysosomal modulators for treating AD either alone or in combination with current treatments, thus providing novel approaches aimed at slowing or reversing AD, as well as delaying or preventing its onset.